5alpha-hydroxy-6beta-azidopregnanes and 5alpha-hydroxy-6beta-aminopregnanes



United States Patent 3,345,363 Su-HYDROXY-GB-AZIDOPREGNANES AND 5a-HYDROXY-QB-AMINOPREGNANES Kanzo Sasaki, Osaka, Japan, assignor toShionogi & Co., Ltd, Osaka, Japan N0 Drawing. Filed July 11, 1963, Ser.No. 294,259 Claims priority, application Japan, July 17, 1962,

6 Claims. (Cl. 260-23955) The present invention relates to 5a-hydroxy-68-azidopregnanes and 5a-hydroxy 6fi-amino-pregnanes. The preparation ofthe latter involves more particularly converting a 5a,6fi-epoxysteroidof the pregnane series into the corresponding5a-hydroxy-6;3-aminosteroid of the pregnane series substantially by twosteps, i.e., ring opening and reduction.

Hitherto, it has been known that simple epoxides can be opened withamines or ammonia [Elielz Steric Effects in Organic Chemistry, p. 106(19 56)]. On the basis of this knowledge, Batres et a]. have succeededin the ring opening of 5a,6ot-epoxysteroids with amines to produce5ot-hydroxy-6p-aminosteroids wherein the amino group is tertiary [Batreset al.: J. Org. Chem., vol. 26, p. 878 1961)]. The present inventor hasattempted to synthesize a steroid having a free amino group and, on thebasis of the said knowledge, to react a 50L,60L-pOXysteroid withammonia. As the result of the attempt, however, only a resinous materialhas been recovered with no production of the objective amine. It has nowbeen discovered that a 5a,6a-epoxysteroid is ring-opened with hydrogenazide or alkali azide and the resuling SOL-hydroxy-6/3-azidosteroidreduced in a per se conventional procedure to give the5ot-hydroxy-6B-aminosteroid. The present invention is based on thisdiscovery.

Accordingly, it is a basic object of the present invention to embody5a-hydroxy-6fl-aminosteroids of the pregnane series which arepharmacologically active. A further object of the invention is to embody5a-hydroxy-6fiazidosteroids of the pregnane series which areintermediates in the said route. Other objects will be apparent to thoseconversant with the art to which the present invention pertains from thesubsequent description.

According to the present invention, the starting 50:, 6a-epoxysteroid ofpregnane series is first subjected to epoxy linkage fission by treatingthe same with hydrogen azide or alkali azide (e.g., sodium azide,potassium azide). The reaction is advantageously carried out in asuitable diluent such as water, methanol, ethanol, ether, dioxane andtetrahydrofuran or in a mixture of two or more such solvents. Thereaction temperature may range, for example, from 80 to 150 C. when thereaction is executed in a sealed tube. The resulting 5a-hydroxy-6/3-azidosteroid of the pregnane series is then subjected to reduction in aper se conventional manner. As the reduction procedure, there may beadvantageously adopted a catalytic reduction procedure or a reductionprocedure using a reducing agent such as metal hydride. When thereduction procedure using a metal hydride (e.g., lithium aluminumhydride, lithium tritertiary butoxy aluminum hydride) is adopted, thereaction may be carried out by treating the 5ot-hydroxy-6B-azidosteroidof the pregnane series with the metal hydride in an inert organicsolvent ice such as ether, tetrahydrofuran and dioxane advantageously ata temperature between room temperature (15 to 30 C.) and the boilingtemperature of the solvent employed.

The resulting Sa-hydroxy-6B-aminosteroid of the pregnane series may be,if necessary, further converted into the corresponding 5ot-hydroxy-68-acylaminosteroid of the pregnane series by a conventional acylationprocedure such as treatment with a lower alkonoic anhydride (e.g.,acetic anhydride, propionic anhydride) and an organic base (e.g.,pyridine, picoline), the latter being sometimes purified more readilythan the former.

The thus-produced 5a-hydroxy-6fi-aminosteroid of the pregnane series andthe 6-acylate thereof are useful as CNS (central nervous system)depressing agents. For instance, 5a-hydroxy-6fi-aminopregnane-3,ZO-dioneinduces anesthetic state in mice, when administered at a non-toxic doseby intraperitoneal route.

The starting 5a,6a-epoxysteroid of the pregnane series may, apart fromthe substituent at the 5- and 6-positions, contain further substituents,such as free or functionally converted hydroxyl, oxo or carboxyl groups,also methyl groups, and it may also contain double bonds. In the courseof the reduction step of the present process, free oxo groups may besimultaneously converted into hydroxyl groups and free and functionallyconverted carboxyl groups into hydroxymethyl groups. If suchsimultaneous conversion is not favorable, the previous protection of theconvertible groups according to a per se conventional manner isrequired. Specific starting materials are, for example,5a,6ot-epoxypregnane-3,20-dione [Ellis et al.: J. Chem. Soc., p. 44171956) 21-hydroxy-5a,6ot-epoxypregnane-3,ZO-dione (1956)], 21 hydroxy5a,6ot-epoxypregnane-3,ZO-dione 21-acetate [Ellis et al.: J. Chem. 800.,p. 4417 (1956)], 1l/3,17a-dihydroxy-21 acetoxy 5u,6u epoxypregnane3,20-dione 3,20-bisethyleneketal [Bernstein et al.: US. Patent2,742,461], 313,21-dihydroxy-5a,6a-epoxypregnan-20- one 2l-acetate[Ellis et al.: J. Chem. Soc., p. 4417 (1956)], 35 hydroxy 5a,6mepoxypregnan 20 one [Ellis et al.: J. Chem. Soc., p. 4417 (1956)],3p-hydroxy-5a,6a-epoxypregnan-20-one 3-acetate [Ellis et al.: J. Chem.'Soc., p. 44 17 (1956)], 3{3,20-dihydroxy-5a,6aepoxypregnane3,20-diacetate [Ringold et al.: J. Org. Chem, vol. 22, p. 99 (1957)],3fi,ZO-d1hYdIOXY-5u,6oc, 1-60c,17a diepoxy-20 pregnene 3,20 diacetate[Slomp: US. Patent 2,751,381], 3/3-hydroxy-5a,6ot epoxy-16-pregnen-ZO-one [Slompz US. Patent 2,751,381],5u,6aepoxypregnane-3,20-dione 3,20-bisethyleneketal [Cooley .et al.: J.Chem 800., p. 4112 (1957)], llot-hydroxy 50c, '60: epoxypregnane 3,20dione 3,20- bisethyleneketal [Cooley et al.: J. Chem. 800., p. 4112(1957], methyl 3,3 bisethylenedioxy 5a,6a-epoxy-l1-oxo-17-pregnen-2J1-oate [Hogg et al.: U.S. Patent 2,841,600], 504,60-epoxypregnane-3,20-dione 3-ethyleneketal [Bowers et al.: Tetrahedron,vol. 7, p. 13.8 (1959)], 17a,21-diacetoxy-5a,6u-epoxypregnane-3,20-dione 3-ethyleneketal [Bowers et al.:Tetrahedron, vol. 7, p. 138 (1959)], etc.

The following examples illustrate presently-preferred embodiments of theinvention. In these examples, each of the abbreviations has theconventional meaning, e.g., mg.=milligram(s), g.=gram(s),ml.=milliliter(s), C.= degrees centrigrade.

Example 1 CH CH3 HO N;

CH3 CH3 HO NHCOCH;

(A) Preparation of 5a-hydroxy-6fl-azidopregnane-3,20- dione3,2O4bisethyleneketal: To a solution of 511,60;-epoxypregnane-3,20-dione 3,20-bisethyleneketal [Bowers et al.:Tetrahedron, vol. 7, p. 138 (1959)] (1.00 g.) in ethanol (8 m1.) anddioxane (1 ml.), there is added a solution of sodium azide (0.48 g.) inWater (3 ml.), and the resultant mixture is heated in a sealed tube for36 hours at 120 C. The reaction mixture is concentrated under reducedpressure to a one-third volume. The resulting concentrated mixture isfiltered to eliminate the precipitated crystals which are those of thestarting material. The filtrate is further concentrated under reducedpressure to give an oil (0.65 g.). The oil is chromatographed on alumina(19 g.). The eluate with benzenepetroleum ether (1 :5 -1:1) isevaporated and the residue crystallized from methanol to give5a-hydroxy-6B-azidopregnane-3,20-dione 3,20-bisethyleneketal (0.32 g.)as crystals melting at 118.5 C.

Analysis.Calcd. for C H O N C, 65.05 H, 8.52 N, 9.10. Found: C, 65.11;H, 8.64; N, 9.10.

(B) Preparation of 5or-hydroxy-6,8-aminopregnane-3, 20-dione3,20-bisethyleneketal: A solution of Sat-hydroxy-6,8-azidopregnane-3,20-dione 3,20-bisethyleneketal (2.59 g.) inanhydrous tetrahydrofuran (60 ml.) is added dropwise to a solution oflithium aluminum hydride (2 g.) in anhydrous ether (60 ml.) at roomtemperature to 30 C.) while stirring, and the resultant mixture isstirred at room temperature for 2.5 hours. The reaction mixture iscombined with ether and water and then shaken with chloroform. Theorganic solvent layer is washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue iscrystallized from methanol to give 5ot-hydroxy-6,8-aminopregnane-3,-dione 3,20-bisethyleneketal (2.35 g.) as crystals melting at 180 to 181C.

Analysis-Calcd, for C H O N: C, 68.93; H, 9.49; N, 3.22. Found: C,68.62; H, 9.53; N, 3.12.

(C) Preparation of 5a-hydroxy-6fi-acetylaminopregnane-3,20-dione3,20-bisethyleneketal: To a mixture of acetic anhydride (2 ml.) andpyridine (10 ml.), there is added 5u-hydr0xy-6B-aminopregnane-3,20-dione3,20- bisethyleneketal (2.41 g.), and the resultant mixture is allowedto stand at room temperature (15 to C.) for 15 hours. The reactionmixture is combined with icewater. The precipitated crystals arecolletced by filtration, washed with water, dried and recrystallizedfrom a mixture of methanol and ether to give Soc-hYdI'OXY-6fi-3C61ZY1- 4aminopregnane-3,20-dione 3,20-bisethyleneketal (1.66 g.) as crystalsmelting at 260.5 to 261.5 C.

Analysis.Calcd. for C H O N: C, 67.89; H, 9.03; N, 2.93. Found: C,67.65; H, 9.24; N, 2.98.

Example 2.

(In the following scheme, the step represented by a dotted line isactually a plurality of steps.)

.- HO N3 (IJHa (A) Preparation of 5a-hydroxy-65-azidopregnane-3,20-dione: 5a,6u-epoxypregnane-3,20-dione [Ellis et a1.: J. Chem. Soc. p.4417 (1956)] is subjected to reaction with sodium azide as in Example 1(A) whereby Soc-hydroxy- -azidopregnane-3,20-dione is produced.Recrystallization of the product from a mixture of acetone and hexanegives crystals melting at 223 to 226 C. (decomp).

Analysis.-Calcd. for C H O N C, 67.53; H, 8.37; N, 11.35. Found: C,67.69; H, 8.53; N, 11.55.

(B) Preparation of 5ot-hydroxy-dfl-aminopregnane-3,- 20-dionez To asolution of 5a-hydroxy-6B-aminopregnane-3,20-dione 3,20-bisethy1eneketal[cf. Example 1 (B)] (2.00 g.) in acetone (50 ml.), there is added amixture of p-toluenesulfonic acid hydrate (1.2 g.) in water (0.3 ml.) innitrogen stream, and the resulting mixture is allowed to stand at about60 C. for 30 minutes. The reaction mixture is combined with water, madealkaline with sodium hydroxide and shaken with chloroform. Thechloroform layer is washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue iscrystallized from a mixture of acetone and ether to give5ot-hydroxy-6fl-aminopregnane- 3,20-dione (535 mg.) as crystals meltingat 235 to 245 C. (decomp).

Analysis.Calcd. for C H O N: C, 72.58; H, 9.57; N, 4.03. Found: C,72.85; H, 9.63; N, 4.31.

(C) Preparation of 500 hydroxy 6B acetylaminopregnane-3,20-dione: In amixture of acetic anhydride (2 ml.) and pyridine 10 ml.), there isdissolved SOL-hydroxy-6fl-aminopregnane3,20-dione (2.35 g.), and theresultant solution is allowed to stand at room temperature (15 to 30 C.)for 15 hours. The reaction mixture is combined with ice-Water. Theprecipitated crystals are collected by filtration, washed with Water,dried and recrystallized from methanol to give5a-hydroxy-6B-acetylaminopregnane-3,20-di0ne (1.72 g.) as crystalsmelting at 244 to 247 C.

Analysis.Calcd. for C H O N.1/2H O: C, 69.31; H, 9.11; N, 3.44. Found:C, 69.32; H, 9.34; N, 3.26.

Example 3 r C=O (A) Preparation of 3 8,5a-dihydroXy-6;8-azidopregnan 20one: 35 hydroxy-5a,6u-epOXypregnan-ZO-One [Ellis et al.: J. Chem. Soc.,p. 4417 (1 956)] is subjected to reaction With sodium azide as inExample 1 (A) whereby 3 6,50; dihydroxy-6fi-azidopregnan-20-one isproduced. Recrystallization of the product from a mixture of ace- 6 toneand petroleum ether gives crystals melting at 198 to 200 C.

Analysis.Calcd. for C H O N C, 67.17; H, 8.86; N, 11.19. Found: C,67.39; H, 8.91; N, 11.05.

(B) Preparation of 3B,5a,2-0 trihydroxy 6fl-aminopregnane: 35,50;dihydroxy 6,8 azidopregnan-ZO-one is subjected to reduction as inExample 1 (B) whereby 3fl,5oc, ZO-trihydroxy-6,8-arninopregnane isproduced.

What is claimed is:

1. 35,5a-dihydroxy-6/8-azidopregnan20-one.

2. 5a-hydroxy-6B-aminopre-gnane-3,20-dione 3,20-bisethyleneketal.

3. 5a-hydroxy-6fi-aminopregnane-3,20 dione.

4. 3[3,5a,ZO-trihydroxy-65-aminopregnane.

5. 5a hydroxy 6/3-acetylaminopregnane-3,20-dione 3,20-bisethy1eneketal.

6. 5a-hydroxy-6B-acetylaminopregnane-3,ZO-dione.

References Cited UNITED STATES PATENTS 2,996,521 8/1961 Mathews et al.260-349' OTHER REFERENCES Boyer et a1.: Alkyl and Aryl Azides, ChemicalReviews, vol. 54, No. 1, Feburary 1954, p. 10.

LEWIS GOTT S, Primary Examiner.

I. R. GENTRY, J. R. BROWN, Assistant Examiners.

2. 5A-HYDROXY-6B-AMINOPREGNANE-3,20-BISETHYLENEKETAL.